Project summary This project investigates whether vestibular loss predicts falls in patients with Alzheimer?s disease (AD). The proposed research is an observational study of 150 patients with AD to evaluate the association between baseline vestibular function and 2-year incidence of falls. We will also explore whether vestibular function is associated with balance and gait function, as well as spatial cognitive function, as potential mechanisms by which vestibular function contributes to fall risk. Specifically, Aim 1 is to determine whether vestibular loss predicts falls in patients with mild-moderate AD. We hypothesize that poorer vestibular function at baseline predicts a higher 2-year incidence of falls. Additionally, we hypothesize that the attributable risk of falls associated with vestibular loss will be substantial enough (>~10%) to warrant further investigation of vestibular therapy as a clinically significant modifier of fall risk. Aim 2 is to evaluate whether vestibular loss in AD predicts impaired static and dynamic balance, measured using the Berg Balance Scale (BBS) and the Timed-Up-and-Go (TUG) test. We hypothesize that greater reduction in vestibular function over the 2-year follow-up period predicts greater decline in BBS and TUG performance. Aim 3 is to evaluate whether vestibular loss in AD predicts impaired spatial cognitive skills. We will administer cognitive tests of spatial cognition (including the Money Road Map test, the Card Rotations test, the Visual Form Discrimination test and the Clock Drawing test), and we will also query participants and caregivers about difficulty with driving, losing objects, getting lost and wandering behaviors as functional manifestations of impaired spatial cognition in AD patients. We hypothesize that greater reduction in vestibular function over the 2-year follow-up period predicts greater decline in spatial cognitive test scores, and a higher incidence of functional spatial cognitive impairment. Moreover, we hypothesize that impaired balance measures (from Aim 2) and impaired spatial cognitive skills will both be independent mediators of the association between vestibular loss and incident falls. To accomplish these aims, we will leverage well-established resources at Johns Hopkins including the Johns Hopkins Alzheimer?s Disease Research Center and the Memory and Alzheimer?s Treatment Center. Falls are a major source of morbidity in AD and current interventions are not uniformly effective. If our observational studies demonstrate that vestibular loss is associated with poorer balance and spatial cognition and incident falls, these results will inform the design of interventional trials to prevent falls in AD patients.